NSAIDs increase urinary retention

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Hi All,

See the not yet in Medline pdf-available description and excerpts of the article

that suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) increase

urinary

retention. Doubling of urinary retention is no small matter, as the condition

is

described in the abstract Background, below.

In This Issue of Archives of Internal Medicine

Arch Intern Med. 2005;165:1454.

Prostaglandins play a role in the micturition pathway as they provoke

contractions

of the urinary bladder. Case reports have suggested that nonsteroidal

anti-inflammatory drugs (NSAIDs), via inhibition of prostaglandin synthesis, may

increase the risk of acute urinary retention. Verhamme et al conducted a

population-based, case-control study among men 45 years and older in the

Integrated

Primary Care Information database, a general practitioner’s research database,

to

study this association. The results indicate that current use of NSAIDs doubles

the

risk of acute urinary retention.

(SEE ARTICLE)

Nonsteroidal Anti-inflammatory Drugs and Increased Risk of Acute Urinary

Retention

Katia M. C. Verhamme; Jeanne P. Dieleman; Marc A. M. Van Wijk; Johan van der

Lei;

ph L. H. R. Bosch; Bruno H. C. Stricker; Miriam C. J. M. Sturkenboom

Arch Intern Med. 2005;165:1547-1551.

ABSTRACT

Background Acute urinary retention (AUR) is characterized by the sudden

inability

to urinate, which is usually extremely painful and requires catheterization.

Prostaglandins play an important role in the genitourinary function as they

provoke

contractions of the detrusor muscle. Relaxation of the detrusor muscle, via the

inhibition of the prostaglandin synthesis, could result in AUR.

Methods We conducted a population-based case-control study within the

Integrated

Primary Care Information project in the Netherlands to investigate whether the

use

of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased

risk of AUR. All men 45 years or older registered in the database between 1995

and

2002 and with at least 6 months of valid history were included. Cases were all

men

with a validated diagnosis of AUR. To each case, up to 10 controls were matched

on

age and calendar time.

Results Within the source population of 72 114 men, we identified 536 cases of

AUR

and 5348 matched controls. Risk of AUR was 2.02-fold higher in current users of

NSAIDs than in nonusers (95% confidence interval, 1.23-3.31). The highest risk

for

AUR (adjusted odds ratio, 3.3; 95% confidence interval, 1.2-9.2) was observed in

patients who recently started using NSAIDs and in those using a dose equal to or

higher than the recommended daily dose.

Conclusion This study shows that the risk of AUR is about 2-fold higher in men

who

use NSAIDs.

INTRODUCTION

Acute urinary retention (AUR) is a condition characterized by the sudden

inability

to urinate, which is usually painful and requires catheterization.1 Mechanisms

such

as increased resistance of the urinary flow, interruption of the sensory

innervation

of the bladder, weakness of the detrusor muscle, and overdistention of the

bladder

are involved in the pathogenesis of AUR.2 The incidence of AUR is higher in men

than

in women, especially in older age categories, because men more often have

comorbidities known to provoke AUR.3

In vitro studies have shown that prostaglandins, especially prostaglandin E2,

play

an important role in the genitourinary function. The prostaglandin synthesis in

the

bladder works via cyclooxygenase-2 (COX-2) and is up-regulated by stimuli such

as

inflammation, trauma, and overdistention. Slow tonic contractions of the bladder

muscle result from these processes enabling the bladder to empty.4-6 As

nonsteroidal

anti-inflammatory drugs (NSAIDs) are known to have a direct effect on

prostaglandin

synthesis, they have been tested in clinical trials for the treatment of

detrusor

instability.7-8 Gruenenfelder et al9 recently reported 3 cases of AUR that

occurred

within 1 week after starting treatment with COX-2 inhibitors, which suggests

that

NSAIDs impair bladder contraction, eventually resulting in AUR. The objective of

the

present case-control study in a population of men 45 years or older was to

investigate whether the use of NSAIDs is associated with an increased risk of

AUR.

.... RESULTS

Within the source population of 72 114 men 45 years or older, we identified 536

definite and 25 possible cases of AUR; the incidence was 2.4 per 1000 man-years

(95%

CI, 2.25-2.65). To avoid false-positive misclassification of the outcome, we

included only the definite cases in our case-control analyses. These 536

definite

AUR cases were matched to 5348 controls.

The mean (SD) age in cases was 73.0 (10.4) years. Compared with controls, case

patients had a higher prevalence of comorbidity such as BPH, prostate cancer,

neurologic disorders, and cancer and more often had a history of urinary tract

infections, constipation, surgery, and immobility (Table 1). Current use of

drugs

with anticholinergic effects, narcotic analgesics, and benzodiazepines was also

higher among case patients than among controls (Table 1).

Table 1. Patient Characteristics and Univariate Association With AUR

.............................................

Characteristic Cases, No. (%) (n = 536) Controls, No. (%) (n = 5348) Matched OR*

(95% CI)

............................................

Comorbidity

BPH 228 (42.5) 966 (18.1) 3.48 (2.88-4.21)

Prostate cancer 52 (9.7) 143 (2.7) 3.88 (2.79-5.40)

UTI 45 (8.4) 14 (0.3) 39.56 (20.44-76.66)

Urolithiasis 2 (0.4) 2 (0.0) 10.0 (1.4-71.0)

Urinary incontinence 22 (4.1) 105 (2.0) 2.15 (1.34-3.46)

Surgery 74 (13.8) 34 (0.6) 23.89 (15.62-36.55)

Constipation 22 (4.1) 23 (0.4) 9.83 (5.44-17.76)

Diabetes mellitus† 51 (9.5) 473 (8.8) 1.08 (0.80-1.46)

Cardiac diseases 176 (32.8) 1491 (27.9) 1.27 (1.05-1.55)

Acute neural injury‡ 3 (0.4) 7 (0.1) 4.3 (1.1-16.6)

Stroke 38 (7.1) 255 (4.8) 1.54 (1.08-2.20)

Dementia 7 (1.3) 48 (0.9) 1.5 (0.7-3.3)

Neurological disorders 12 (2.2) 61 (1.1) 1.97 (1.05-3.70)

Cancer 39 (7.3) 165 (3.1) 2.48 (1.72-3.56)

Immobility 159 (29.7) 476 (8.9) 5.43 (4.30-6.86)

Concomitant medication

Anticholinergic drugs 57 (10.6) 356 (6.7) 1.80 (1.33-2.43)

Narcotic analgesics 28 (5.2) 62 (1.2) 4.61 (2.93-7.26)

Benzodiazepines 49 (9.1) 310 (5.8) 1.68 (1.22-2.31)

...............................................

Abbreviations: AUR, acute urinary retention; BPH, benign prostatic hyperplasia;

CI,

confidence interval; OR, odds ratio; UTI, urinary tract infection.

*Matched by year of birth and index date.

†Risk of AUR was increased in patients with long-lasting type 1 diabetes

mellitus

(matched OR, 4.1 [95% CI, 1.3-13.5]).

‡Defined as acute lumbar disc herniation or canal stenosis with neural deficit.

The unadjusted odds ratio (OR) for AUR was 2.26 (95% CI, 1.49-3.45) for current

use

of NSAIDs compared with no use. This increase in risk remained after adjustment

for

other AUR risk factors (OR, 2.02; 95% CI, 1.23-3.31) (Table 2). Past use of

NSAIDs

was not associated with an increased risk of AUR. Among current users, the risk

was

highest for persons who were new NSAIDs users (adjusted OR, 3.3; 95% CI,

1.2-9.2),

whereas the risk for long-term users was 1.77 (95% CI, 1.01-3.10) (Table 2).

The risk of AUR was not linearly related with dose. No association with current

use

of low doses of NSAIDs (<1 DDD) was observed, and there was a similar increase

in

risk for patients taking NSAIDs at a dose of 1 DDD or higher (Table 2).

In a further attempt to explore whether any potential effect would be restricted

to

NSAIDs with high affinity for COX-2, we estimated the AUR risk for the

COX-2–selective inhibiting NSAIDs and the nonselective NSAIDs. Use of

COX-2–selective inhibitors was associated with a somewhat higher risk of AUR

than

use of nonselective NSAIDs, although the difference was not statistically

significant (Table 3).

Table 2. Use of NSAIDs, Excluding Acetylsalicylic Acid, and Risk of AUR

................................................

NSAID Use Status AUR Cases, No. (%) (n = 5348) Controls, No. (%) (n = 536)

Matched

OR* (95% CI) Adjusted OR† (95% CI)

...............................................

No use 448 (83.6) 4715 (88.2) Reference Reference

Current use 28 (5.2) 131 (2.4) 2.26 (1.49-3.45) 2.02 (1.23-3.31)

Past use 60 (11.2) 502 (9.4) 1.26 (0.95-1.67) 0.98 (0.70-1.37)

Duration of use

No use 448 (83.6) 4715 (88.2) Reference Reference

Current use

Started within 1 wk 6 (1.1) 16 (0.3) 3.9 (1.5-9.9) 3.3 (1.2-9.2)

Started >1 wk prior 22 (4.1) 115 (2.2) 2.02 (1.27-3.24) 1.77 (1.01-3.10)

Past use 60 (11.2) 502 (9.4) 1.26 (0.95-1.67) 0.98 (0.70-1.37)

NSAID DDD

No use 448 (83.6) 4715 (88.2) Reference Reference

Current use

<1 DDD 3 (0.5) 41 (0.7) 0.8 (0.2-2.5) 0.7 (0.2-2.6)

1 DDD 12 (2.2) 45 (0.8) 2.82 (1.48-5.37) 2.60 (1.24-5.46)

>1 DDD 13 (2.4) 45 (0.8) 3.10 (1.65-5.83) 2.55 (1.21-5.39)

...................................................

Past use 60 (11.2) 502 (9.4) 1.26 (0.94-1.67) 0.99 (0.70-1.38)

Abbreviations: AUR, acute urinary retention; BPH, benign prostatic hyperplasia;

CI,

confidence interval; DDD, defined daily dose; NSAID, nonsteroidal

anti-inflammatory

drug; OR, odds ratio; UTI, urinary tract infection.

*Matched for year of birth and index date.

†Adjusted for BPH, prostate cancer, UTI, surgery, immobility, and use of

narcotic

analgesics and benzodiazepines.

Table 3. Type of NSAID or Acetylsalicylic Acid and Risk of AUR NSAID Use Status

and

Type

..................................................

AUR Cases, No. (%) (n = 536) Controls, No. (%) (n = 5348) Matched OR* (95% CI)

Adjusted OR† (95% CI)

..................................................

No use 448 (83.6) 4715 (88.2) Reference Reference

Current use

COX-2 selective 3 (0.6) 8 (0.1) 4.4 (1.1-17.9) 3.1 (0.5-17.6)

Non–COX-2 selective 25 (4.7) 123 (2.3) 2.15 (1.38-3.34) 1.96 (1.17-3.26)

Past use 60 (11.2) 502 (9.4) 1.26 (0.95-1.68) 0.96 (0.70-1.37)

Acetylsalicylic acid

Current use 90 (16.8) 756 (14.1) 1.25 (0.98-1.60) 0.99 (0.74-1.32)

Past use 30 (5.6) 257 (4.8) 1.22 (0.83-1.81) 0.86 (0.54-1.38)

..................................................

Abbreviations: AUR, acute urinary retention; BPH, benign prostatic hyperplasia;

CI,

confidence interval; COX-2, cyclooxygenase-2; DDD, defined daily dose; NSAID,

nonsteroidal anti-inflammatory drug; OR, odds ratio; UTI, urinary tract

infection.

*Matched for year of birth and index date.

†Adjusted for BPH, prostate cancer, UTI, surgery, immobility, and use of

narcotic

analgesics and benzodiazepines.

Table 3. Type of NSAID or Acetylsalicylic Acid and Risk of AUR NSAID Use Status

and

Type

.................................................

AUR Cases, No. (%) (n = 536) Controls, No. (%) (n = 5348) Matched OR* (95% CI)

Adjusted OR† (95% CI)

.................................................

No use 448 (83.6) 4715 (88.2) Reference Reference

Current use

COX-2 selective 3 (0.6) 8 (0.1) 4.4 (1.1-17.9) 3.1 (0.5-17.6)

Non–COX-2 selective 25 (4.7) 123 (2.3) 2.15 (1.38-3.34) 1.96 (1.17-3.26)

Past use 60 (11.2) 502 (9.4) 1.26 (0.95-1.68) 0.96 (0.70-1.37)

Acetylsalicylic acid

Current use 90 (16.8) 756 (14.1) 1.25 (0.98-1.60) 0.99 (0.74-1.32)

Past use 30 (5.6) 257 (4.8) 1.22 (0.83-1.81) 0.86 (0.54-1.38)

......................................................

Abbreviations: AUR, acute urinary retention; BPH, benign prostatic hyperplasia;

CI,

confidence interval; COX-2, cyclooxygenase-2; DDD, defined daily dose; NSAID,

nonsteroidal anti-inflammatory drug; OR, odds ratio; UTI, urinary tract

infection.

*Matched for year of birth and index date.

†Adjusted for BPH, prostate cancer, UTI, surgery, immobility, and use of

narcotic

analgesics and benzodiazepines.

The risk of developing AUR in patients currently using acetylsalicylic acid was

not

increased (OR, 1.25; 95% CI, 0.98-1.60). However, most people (95%) used it in

low

doses (<100 mg) (Table 3).

The indications for NSAID use were not substantially different between case

patients

and controls: in more than 70% of each group, the NSAIDs were used to relieve

locomotoric pain. Among the case patients, none of the recent starters of NSAIDs

had

a urologic condition or an acute neural injury as an indication to start

treatment.

We explored effect modification by age, presence of urinary tract infection,

history

of BPH, prostate cancer, and use of concomitant medication such as

anticholinergic

agents or narcotics. We did not identify significant effect modification by any

of

these variables.

Finally, based on an AUR incidence rate of 4.73 per 1000 man-years among the

exposed

and 2.34 per 1000 man-years among the unexposed, we calculated a PAR of 57.4 per

million population per year. Using demographic data from the Dutch Central

Bureau of

Statistics and based on an overall AUR incidence rate of 2.4 per 1000 man-years

in

men 45 years or older, this would mean that for 1998, 6548 new cases of AUR were

expected in men 45 years or older, of which 156 (2.4%) could be attributed to

the

current use of NSAIDs.

COMMENT

In this study, we showed that current use of NSAIDs is associated with an

increased

risk of AUR. The risk is highest in patients who recently started using NSAIDs

and

those who use high daily dosages. To our knowledge, this is the first

epidemiologic

study to report the association between the use of NSAIDs and the risk of AUR.

The

hypothesis as postulated by Gruenenfelder et al9 was that the inhibition of

COX-2

might result in AUR. We observed an increased risk, not only for the

COX-2–selective

inhibitors but also for the nonselective NSAIDs, and after adjusting for all

risk

factors, the increased risk remained only for nonselective NSAIDs. The fact that

the

relationship is not restricted to the current use of COX-2–selective inhibitors

seems plausible, since COX-2 will be inhibited by both COX-2–specific inhibitors

and

nonselective NSAIDs.5 We did not find an association between current use of

acetylsalicylic acid and the risk to develop AUR, probably because

acetylsalicylic

acid was mainly used at low cardioprotective doses and thus had minimal

anti-inflammatory activity.

Although we found an association between the use of NSAIDs and risk of AUR in

this

population-based study, our results must be interpreted with caution. Our

exposure

assessment was based on longitudinally collected general practitioner

prescriptions

rather than dispensing or patient-reported intake and did not include use of

over-the-counter medications. Therefore, we may have misclassified at least some

of

the exposure to NSAIDs. However, it is likely that the exposure

misclassification

was nondifferential, and thus the reported risk estimate was an underestimate.

To

avoid misclassification of the outcome, we manually validated all cases and

included

only definite cases of AUR in our analysis. In addition, the physicians who

reviewed

and classified the cases were blinded to the patient’s drug exposure. Diagnostic

bias was limited because the first case reports on a possible association

between

the use of NSAIDs and AUR were published in September 2002 and, moreover, a

diagnosis of AUR was unlikely to be missed.

Confounding by indication could be a concern in this study because NSAIDs are

used

for the treatment of various urologic conditions (eg, urinary tract infections

and

nephrolithiasis) or acute neural injury (eg, acute lumbar disc herniation or

symptomatic lumbar spinal canal stenosis), which by themselves could precipitate

AUR.16-17 To control for confounding by indication, we checked the indication

for

all current use of NSAIDs in both cases and controls. Only 1 patient among the

cases

used NSAIDs for a urologic condition (chronic prostatitis), and this patient

initiated therapy months prior to the index date, which suggests little or no

influence of confounding by indication. Among the case patients, 3 were

diagnosed as

having acute neural injury in the 1 month prior to the index date. None of these

3

patients received an NSAID but instead were treated with strict bed rest and

paracetamol. The highest risk of AUR that was found among recent users of NSAIDs

was

probably not confounded by indication because none of these patients used NSAIDs

for

urologic conditions or acute neural injury.

All known risk factors for AUR were considered potential confounders, but

residual

confounding by unknown risk factors for which we did not control might remain.

Although we observed that the risk of AUR was about 2-fold higher in male

patients

currently using NSAIDs than in those not taking NSAIDs, there have been numerous

reports on various medical conditions and use of concomitant medications that

note a

higher risk of provoking AUR.18 Particularly, narcotic agents and drugs with

anticholinergic effects increase the risk of AUR. Medical conditions associated

with

an increased risk of AUR are mainly those that increase the resistance to the

urinary flow (eg, BPH, prostate cancer, urethral stricture, and constipation).

In

addition, surgery, homebound lifestyle, and various neurologic conditions

increase

the risk of AUR. In our study, we confirmed these other risk factors for AUR,

and we

observed that patients using narcotic analgesics were especially at risk for

developing AUR.

Acute urinary retention occurs mainly in aging men as a consequence of

comorbidity

and the use of concomitant medications. In our study, we found that the risk of

AUR

is about 2-fold higher in patients currently using NSAIDs than in those not

taking

NSAIDs. We believe that physicians should be informed about the possibility of

provoking AUR in patients using NSAIDs, especially in high-risk patients.

Al Pater, PhD; email: old542000@...

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